A variety of environmental pollutants are known to affect renal function. In addition, several naturally occurring substances, primarily secondary products of fungal metabolism, also adversely affect the kidney. Circumstantial evidence suggests that the fungal toxins may be involved in the production of the fatal human disease, endemic Balkan nephropathy. Specifically, ochratoxin A has been suggested as the causative agent and ochratoxin A and/or Citrinin have been shown to produce a similar disease in pigs, i.e., porcine nephropathy. Whether one fungal toxin or a combination of agents might produce these diseases in the field situation is unkown. Therefore, it is the intent of this proposal to examine the interaction of certain fungal toxins and of other environmental pollutants with fungal toxins in the production of an experimental mycotoxin-induced nephropathy in the laboratoary rat. In particulr, ochratoxin A, citrinin, rubratoxin B, etc., and manmade pollutants such as certain mercury salts, chromium salts or halogenated hydrocarbons will be studies. Both Sprague-Dawley rats and the Fisher 344 rats (suggested to be more sensitive to nephrotoxic insult) will be used in these studies. The specific combinations of agents to be investigated will be paired both on the basis of natural occurrence and because they affect either the same or different nepthron segments, e.g., citrinin affects the pars convoluta, hexachlorobutadiene the pars recta. Chromium has a primary effect on the pars convolutat and mercury on the pars recta. Dose respons relationships will be examined wherein low doses as well as high doses of each of the combinations of agents will be tested. Both whole animal experiemtns (unanesthe=tized animals in metabolism cages and anesthetized animals for clearnce experiments) and in vitro renal slice studies will be used. the renal slice experiments will be designe to assess the transport of organic ions and various inorganic electrolytes. The isolated perfused kidney will be used as necessary to demonstrate the presence of intrarenally formed metabolites. The overall role of metabolism will be examined by the use of glutathione depleting agents, e.g., DEM, and stimulators and inhibitors of the mixed function oxidase metabolizing systems (B-naphaflavone; phenobarbital; SKF-5r25A; piperonylbutoxide).